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首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Fourth-generation model for corticosteroid pharmacodynamics: a model for methylprednisolone effects on receptor/gene-mediated glucocorticoid receptor down-regulation and tyrosine aminotransferase induction in rat liver.
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Fourth-generation model for corticosteroid pharmacodynamics: a model for methylprednisolone effects on receptor/gene-mediated glucocorticoid receptor down-regulation and tyrosine aminotransferase induction in rat liver.

机译：皮质类固醇药代动力学的第四代模型：甲基强的松龙对大鼠肝脏中受体/基因介导的糖皮质激素受体下调和酪氨酸氨基转移酶诱导作用的模型。

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A fourth-generation pharmacokinetic/pharmacodynamic (PK/PD) model for receptor/genemediated effects of corticosteroids was developed. Male adrenalectomized Wistar rats received a 50 mg/kg i.v. bolus dose of methylprednisolone (MPL). Plasma concentrations of MPL, hepatic glucocorticoid receptor (GR) messenger RNA (mRNA) and GR density, tyrosine amino-transferase (TAT) mRNA, and TAT activity in liver were determined at various time points up to 72 hr after MPL dosing. Down-regulation of GR mRNA and GR density were observed: GR mRNA level declined to 45-50% of the baseline in 8-10 hr, and slowly returned to predose level in about 3 days; GR density fell to 0 soon after dosing and returned to the baseline in two phases. The first phase, occurring in the first 10 hr, entailed recovery from 0 to 30%. The second phase was parallel to the GR mRNA recovery phase. Two indirect response models were applied for GR mRNA dynamics regulated by activated steroid-receptor complex. A full PK/PD model for GR mRNA/GR down-regulation was proposed, including GR recycling theory. TAT mRNA began to increase at about 1.5 hr, reached the maximum at about 5.5 hr, and declined to the baseline at about 14 hr after MPL dosing. TAT induction followed a similar pattern with a delay of about 1-2 hr. A transcription compartment was applied as one of the cascade events leading to TAT mRNA and TAT induction. Pharmacodynamic parameters were obtained by fitting seven differential equations piecewise using the maximum likelihood method in the ADAPT II program. This model can describe GR down-regulation and the precursor/product relationship between TAT mRNA and TAT in receptor/gene-mediated corticosteroid effects.
机译：建立了皮质类固醇受体/基因介导作用的第四代药代动力学/药效学（PK / PD）模型。雄性肾上腺切除的Wistar大鼠静脉内接受50mg / kg。大剂量甲基强的松龙（MPL）。在MPL给药后直至72小时的各个时间点，测定肝脏中MPL的血浆浓度，肝糖皮质激素受体（GR）信使RNA（mRNA）和GR密度，酪氨酸氨基转移酶（TAT）mRNA和TAT活性。观察到GR mRNA和GR密度的下调：GR mRNA水平在8-10小时内下降至基线的45-50％，并在约3天内缓慢恢复至给药前水平。给药后GR密度很快降至0，并分两个阶段返回基线。在最初的10小时内发生的第一阶段需要从0％恢复到30％。第二阶段与GR mRNA恢复阶段平行。两种间接反应模型适用于激活的类固醇受体复合物调节的GR mRNA动态。提出了一个完整的PK / PD模型，用于GR mRNA / GR的下调，包括GR回收理论。 TAT mRNA在约1.5小时开始增加，在约5.5小时达到最大值，并在MPL给药后约14小时下降至基线。 TAT诱导遵循类似的模式，延迟约1-2小时。转录区室被用作导致TAT mRNA和TAT诱导的级联事件之一。通过在ADAPT II程序中使用最大似然法分段拟合七个微分方程来获得药效学参数。该模型可以描述GR下调以及受体/基因介导的糖皮质激素作用中TAT mRNA和TAT之间的前体/产物关系。

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